Overview
Scarring and tightening (tissue contraction) are part of the process of wound healing. They play a part in almost every major blinding disease, either in the condition itself or in whether treatment will fail. They are the main reason for glaucoma surgery to fail.
Certain non-licensed medicines can prevent scars forming but can have significant side-effects, including blindness. There aren’t licensed treatments yet that could improve the results of surgery, so we need to understand more about tissue contraction and scarring.
The research team has found that a small protein called Rac1 becomes active when tissue contracts. If you block Rac1 from working, tissue doesn’t contract. So blocking Rac1 might be able to prevent long-term scarring in the eye.
In this project the team is studying how the Rac1 protein makes tissue contract and how best to block it. They also want to know whether blocking Rac1 prevents scars forming. The information could lead to treatment that could improve outcomes in major blinding conditions such as glaucoma. The result might also be important for certain other conditions that involve tissue contraction and scarring, for example in the heart and lungs.
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Publications
- Li H, Roos JCP, Rose GE, Bailly M, Ezra DG. Eyelid and Sternum Fibroblasts Differ in Their Contraction Potential and Responses to Inflammatory Cytokines: Plastic and Reconstructive Surgery - Global Open. 2015 Jul;3(7):e448.
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Research update
So far, the team has found that the there’s a dramatic change in which genes are active early on in the process of tissue contraction. Blocking the Rac1 protein stops this dramatic change from happening, so it seems that Rac1 controls a complex system. They have also investigated several candidates that can block Rac1, that might be suitable for developing a new anti-scarring treatment. -
Scientific summary
The small Rho GTPase Rac1 as a therapeutic target to prevent scarring
Tissue contraction and scarring processes play a part in the pathogenesis or failure of treatment of virtually every major blinding disease, with postsurgical scarring being the main cause of failure for glaucoma surgery. Anti-mitotic agents applied off label at the time of the surgery have proved successful in preventing fibrosis but still carry significant side effects that can lead to blindness, and there is currently no licensed treatment available to prevent scarring and improve the outcome of the surgery. There is thus a strong need to better understand the biology of tissue contraction and scarring and identify suitable targets and delivery mode for therapy.
We have developed a range of in vitro and ex-vivo models of conjunctiva contraction that allowed us to identify the small GTPase signalling pathways, and particularly Rac1, as major regulators of tissue contraction. This project proposes to use our models to characterize the role of Rac1 in tissue contraction and fibrosis, identify the main pathways involved through a detailed analysis of our recently obtained microarray data and perform a pilot in vivo study in our rabbit model of glaucoma filtration surgery using local delivery of a Rac1 inhibitor to evaluate its potential as a new target for anti-scarring treatments.